About POLE
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLE c.4189C>A, p.(Leu1397Ile)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is León-Castillo et al. 2020 custom POLE framework. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_006231.3:c.4189C>A (p.Leu1397Ile) is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, indicating it is not observed in large population cohorts.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Only one criterion is met: PM2 at Supporting strength (absent from gnomAD v2.1, v4.1, and gnomAD-Canada). No pathogenic, likely pathogenic, benign, or likely benign combination threshold is satisfied under ACMG/AMP 2015 rules. Per the León-Castillo et al. 2020 custom POLE framework, criterion triggering and strength are customized (PM1, PS4, PP3, BP4), but final classification combination follows standard ACMG/AMP 2015 thresholds, which explicitly state that all other combinations default to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. POLE, the catalytic subunit of DNA polymerase epsilon, is an enzyme involved in DNA replication and repair. Select POLE mutations lead to ultra-high m
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under León-Castillo et al. 2020 custom POLE framework, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 21 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_006231.3:c.4189C>A (p.Leu1397Ile) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at Supporting strength.
No other pathogenic or benign criteria are met. The variant is a C-terminal missense change outside the exonuclease domain, with no functional data, no clinical observations, no segregation data, and indeterminate computational predictions (REVEL 0.329, BayesDel -0.262).
With only PM2_Supporting met, the evidence is insufficient to classify this variant as pathogenic or likely pathogenic, and insufficient to classify as benign or likely benign. This variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.
No criteria match.
Met · 1
PM2 SupportingNM_006231.3:c.4189C>A (p.Leu1397Ile) is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, indicating it is not observed in large population cohorts. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- gnomAD v4.1 (0 alleles)
- and gnomAD-Canada v1.0 (0 alleles).
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No pathogenic missense variant has been identified at codon 1397. The variant is absent from ClinVar, and no same-residue pathogenic comparator exists in the literature or curated databases. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no same-codon pathogenic variants identified.
Sources
clinvar ↗pm5_candidates
PS2 No de novo observations have been reported for NM_006231.3:c.4189C>A. No family or parent-of-origin data are available. Details ▾Hide ▴
Evidence considered
- No de novo data available for this variant.
Still missing
- No parental testing or de novo analysis has been performed.
PS3 No functional studies have been performed on p.Leu1397Ile or a systematically characterized range that includes residue 1397. OncoKB reports Unknown Oncogenic Effect. Position 1397 is far C-terminal, well outside the exonuclease domain (residues ~268–471), and not covered by any known tiling/saturation mutagenesis dataset. Details ▾Hide ▴
Evidence considered
- OncoKB reports Unknown Oncogenic Effect
- no experimental functional data identified for this variant or a systematically characterized region including residue 1397.
Still missing
- No variant-specific or range-based functional assays available.
Sources
PS4 The variant is absent from the León-Castillo Supplementary Table S1 and is not recurrent in COSMIC or TCGA endometrial carcinoma cohorts. Custom PS4_Supporting requires recurrence in both cohorts with combined EC count ≥10 and membership in the established pathogenic set, which are not met. No germline case-control enrichment data exist. Details ▾Hide ▴
Evidence considered
- Variant absent from COSMIC
- ClinVar
- and VCEP Supplementary Table S1
- zero somatic recurrence.
Still missing
- No case-control or cohort enrichment data available.
Sources
vcep_path_250_323_s002clinvar ↗
PM1 Residue 1397 is in the C-terminal region of POLE, well outside the exonuclease domain (residues ~268–471). The León-Castillo custom PM1 framework applies only to five established exonuclease-domain hotspots (P286R, V411L, S297F, A456P, S459F) and specific recurrent pathogenic or uncertain-tier variants, none of which include p.Leu1397Ile. Position 1397 is not in a known functional domain or mutational hotspot. Details ▾Hide ▴
Evidence considered
- Position 1397 is C-terminal
- outside the exonuclease domain
- not a cancerhotspots.org hotspot
- absent from VCEP S1 hotspot list.
Sources
vcep_path_250_323_s002
PM6 No de novo observations of NM_006231.3:c.4189C>A have been reported. No parent-of-origin or confirmed maternity/paternity data are available. Details ▾Hide ▴
Evidence considered
- No de novo data available for this variant.
Still missing
- No de novo testing or trio analysis data.
PP1 No segregation data are available for NM_006231.3:c.4189C>A. The variant has not been observed in families with disease, and no co-segregation analysis has been performed. Details ▾Hide ▴
Evidence considered
- No segregation or family data available.
Still missing
- No family studies or segregation analysis.
PP2 No HCI prior score is available for this variant. While POLE has disease-associated missense variants in the exonuclease domain, residue 1397 is in a C-terminal region with unknown functional significance, and REVEL score (0.329) is indeterminate. Insufficient evidence to apply PP2. Details ▾Hide ▴
Evidence considered
- HCI prior not found
- REVEL 0.329 indeterminate
- position 1397 is C-terminal with no established disease association.
Still missing
- No HCI prior score for this gene/region.
Sources
revelbayesdel
PP3 The variant is absent from León-Castillo Supplementary Tables S2 and S3, so the custom PP3_Supporting rule does not apply. Under generic in silico assessment: REVEL score 0.329 is indeterminate (below pathogenic threshold of ~0.5), BayesDel score -0.262205 leans benign, and SpliceAI predicts no splicing impact (max delta 0.01). Multiple computational lines do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.329 (indeterminate)
- BayesDel -0.262205 (benign-leaning)
- SpliceAI max delta 0.01 (no splicing impact)
- variant absent from VCEP S2/S3.
Sources
PP4 No clinical phenotype data are available for NM_006231.3:c.4189C>A. The variant has not been reported in affected individuals, and no phenotype specificity analysis can be performed. Details ▾Hide ▴
Evidence considered
- No phenotype or clinical data available for this variant.
Still missing
- No clinical case data or phenotype reports.
PP5 No reputable source has classified NM_006231.3:c.4189C>A as pathogenic. The variant is absent from ClinVar and has not been evaluated by any expert panel. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no expert panel or reputable source classification.
Sources
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency of 0 does not meet the >1% threshold for BA1. Details ▾Hide ▴
Evidence considered
- Absent from all population databases
- allele frequency 0%
- below BA1 threshold of >1%.
Sources
BS1 The variant is absent from all population databases. Allele frequency of 0 does not meet the >0.3% threshold for BS1; BS1 requires the variant to be observed at a frequency too high for a disease-causing variant. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD
- allele frequency 0%
- below BS1 threshold of >0.3%.
Sources
BS2 No homozygous or compound heterozygous observations of NM_006231.3:c.4189C>A have been reported. The variant is absent from gnomAD, so no homozygote count data exist. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- no homozygote or compound heterozygote observations.
Sources
BS3 No functional studies have been performed demonstrating a benign effect for p.Leu1397Ile. No variant-specific or range-based experimental data are available to assess functional impact. Details ▾Hide ▴
Evidence considered
- OncoKB reports Unknown Oncogenic Effect
- no functional studies demonstrating neutral/benign effect.
Still missing
- No functional assays available for this variant.
Sources
BS4 No segregation or family data are available for NM_006231.3:c.4189C>A. Lack of cosegregation with disease in affected families cannot be assessed. Details ▾Hide ▴
Evidence considered
- No segregation or family data available.
Still missing
- No family studies or non-segregation analysis.
BP1 Although this is a missense variant, POLE disease mechanism is not restricted to loss-of-function/truncating variants. Pathogenic missense variants in the exonuclease domain (e.g., P286R, V411L) are well-established in somatic disease. BP1 is not applicable when the gene's disease mechanism includes missense changes. Details ▾Hide ▴
Evidence considered
- POLE disease mechanism includes pathogenic missense variants (e.g.
- P286R
- V411L)
- BP1 not applicable.
Sources
vcep_path_250_323
BP2 No co-occurrence data are available. The variant has not been observed in trans with a known pathogenic POLE variant, nor has it been observed in cis with a pathogenic variant in any reported case. Details ▾Hide ▴
Evidence considered
- No co-occurrence observations with pathogenic variants.
Still missing
- No phase or co-occurrence data.
BP4 The variant is absent from León-Castillo Supplementary Tables S2 and S3, so the custom BP4_Supporting rule does not apply. Under generic in silico assessment: REVEL score 0.329 is indeterminate (neither clearly benign nor clearly pathogenic), BayesDel -0.262205 is mildly benign-leaning, and SpliceAI predicts no splicing impact. The computational evidence is equivocal and does not meet the threshold for BP4, which requires multiple lines of computational evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
- REVEL 0.329 (indeterminate)
- BayesDel -0.262205 (mildly benign-leaning)
- SpliceAI no impact
- variant absent from VCEP S2/S3.
Sources
BP5 No reputable source has classified NM_006231.3:c.4189C>A as benign. The variant is absent from ClinVar and has not been reported in any curated clinical database. Details ▾Hide ▴
BP6 No reputable source has classified NM_006231.3:c.4189C>A as benign. The variant is absent from ClinVar and has no expert panel benign classification. Details ▾Hide ▴
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Leu1397Ile), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 framework per PMC6185798 does not apply to missense substitutions. Details ▾Hide ▴
Evidence considered
- Missense substitution c.4189C>A (p.Leu1397Ile) does not fall into null-variant buckets.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM5 N/ANo same-residue comparator variants were identified. Automated PM5 candidate harvesting was unable to confirm classic same-residue semantics for p.Leu1397Ile. Details ▾Hide ▴
Evidence considered
- No same-codon comparator variants found
- PM5 candidate search returned no candidates.
Sources
pm5_candidates
BP7 N/AThis is a missense variant (c.4189C>A, p.Leu1397Ile), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 only applies to synonymous variants.
PS5 N/AThis variant is absent from ClinVar and has no prior ClinGen-approved pathogenic classification to evaluate. Details ▾Hide ▴
Identifiers
- Gene
- POLE
- Transcript
- NM_006231.3
- Coding (HGVS c.)
- NM_006231.3:c.4189C>A
- Protein (HGVS p.)
- NP_006222.2:p.(Leu1397Ile)
- GRCh38
- chr12:132643938 G>T
- GRCh37
- chr12:133220524 G>T
Gene diagram
Every interpreted variant in POLE, mapped onto the exon structure of NM_006231.3. Select a row to find it on the plot.
POLENM_006231.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in POLE
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.329
- BayesDel
- -0.262
How the predictions were used
PP3 The variant is absent from León-Castillo Supplementary Tables S2 and S3, so the custom PP3_Supporting rule does not apply. Under generic in silico assessment: REVEL score 0.329 is indeterminate (below pathogenic threshold of ~0.5), BayesDel score -0.262205 leans benign, and SpliceAI predicts no splicing impact (max delta 0.01). Multiple computational lines do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.329 (indeterminate)
- BayesDel -0.262205 (benign-leaning)
- SpliceAI max delta 0.01 (no splicing impact)
- variant absent from VCEP S2/S3.
Sources
BP4 The variant is absent from León-Castillo Supplementary Tables S2 and S3, so the custom BP4_Supporting rule does not apply. Under generic in silico assessment: REVEL score 0.329 is indeterminate (neither clearly benign nor clearly pathogenic), BayesDel -0.262205 is mildly benign-leaning, and SpliceAI predicts no splicing impact. The computational evidence is equivocal and does not meet the threshold for BP4, which requires multiple lines of computational evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
- REVEL 0.329 (indeterminate)
- BayesDel -0.262205 (mildly benign-leaning)
- SpliceAI no impact
- variant absent from VCEP S2/S3.
Sources
BP7 N/AThis is a missense variant (c.4189C>A, p.Leu1397Ile), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 only applies to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.329. BayesDel score = -0.262205.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_006231.3%3Ac.4189C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-133220524-G-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-132643938-G-T?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-132643938-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006231.3%3Ac.4189…
- OncoKB ↗www.oncokb.org/gene/POLE/L1397I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLE+c.4189C%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.329. BayesDel score = -0.262205.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. POLE, the catalytic subunit of DNA polymerase epsilon, is an enzyme involved in DNA replication and repair. Select POLE mutations lead to ultra-high m
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.